We plan to analyze: (a) whether metastatic cells possess cell-surface antigens different from those of the local tumor; (b) whether immunoselective processes participate in the control of metastatic spread, and (c ) what are the mechanisms through which the local tumor exerts a suppressive effect on the growth of its metastases? Lymphocytes will be sensitized in culture on monolayers of tumor cells deriving from the local and from the metastatic populations. Cross testing of CL will indicate how general is the phenomenon of antigenic differences between the two cell populations found in the 3LL tumor. The generation in culture of antimetastatic CL will provide a starting point for experiments on adoptive immunity against metastatic progression. Tests of populations of tumors grown in immunosuppressed animals will indicate whether immunoselection plays a role in metastatic spread. We shall further study our observation that metastatic cells are more resistant to NK activity and examine whether selection of NK-resistant cells is associated with an increase in their capacity to produce metastasis. The question of whether metastatic cells differ in their capacity to produce metastasis. The question of whether metastatic cells differ in their expression of H-2 determinants is relevant to the question of the recognition of the cell surface antigens of metastatic cells, by the host syngeneic lymphocytes. Hence, studies will be made using also the T-10 tumor which was produced in an F1 hybrid to test for H-2 restrictions specific for metastatic cells, as distinct from the local cells. The suppressive effect of the local tumor on the progression of its metastases will be studied, aiming mainly at defining immunological versus nonimmunological mechanisms. The fact that acceleration of metastatic progression following excision of the local tumor takes place even in immunosuppressed animals suggests a nonimmune mechanism. The possibility that the tumor secretes factors which suppress nonspecifically cell proliferation will be investigated by testing the effects of tumor growth on hemopoiesis, liver generation and skin mitosis. Concomitantly, factors from tumor cells will be isolated and tested for their effects, in vivo, in suppressing metastasis progression in tumor-excised animals.